5-LO is an enzyme involved in the arachidonic acid metabolism. It synthesizes leukotriene by acting on the generation of 5-HPETE from arachidonic acid. LTB4, the most powerful chemoattractant among synthesized leukotrienes, is a major cause of several diseases such as chronic inflammation, rheumatoid arthritis, allergy, asthma and psoriasis. When the cell content of leukotriene increases, inflammatory cells are activated, causing such inflammatory diseases as chronic inflammation and rheumatism. Also, endotoxins resulting from tissue damage or bacterial infection cause acute or chronical damage of the corresponding tissue and organ.
Therefore, by developing a 5-LO inhibitor capable of preventing tissue and organ damages by inhibiting the activation of inflammatory cells caused by the increase in cellular leukotriene, it is possible to prevent or treat several inflammation-related diseases.
Since some natural products and synthetic compounds having a 2′-sulfonamidomethylbenzopyran backbone show an antioxidant activity, they have been widely known as a privileged structure for developing a pharmacological therapeutic compound effective for treating nerve diseases, hypertension and diabetes and broadly employed in the medicinal chemistry field. However, there is no report that a compound having 2′-sulfonamidomethylbenzopyran moiety as a privileged structure has been developed as an anti-inflammatory agent.
Construction of a benzopyran library having various derivatives using the combinatorial chemical synthetic technique can be effectively used for screening biological hit compounds and lead compounds at the early stage of a noble drug development.
Particularly, it is very important to efficiently construct a large and focused library of small organic molecules, which enable introduction of various derivatives without significantly deviating from the range of Rule of 5 by Lipinsky, with regard to molecular varieties effective for screening lead compounds.
The combinatorial chemical synthesis is a new synthetic method for developing a new compound. While the conventional organic synthetic methods can synthesize one kind of compound via a single reaction, the combinatorial chemical synthetic technique is a highly efficient method which can synthesize more various and numerous compounds at the same time or automate the multi-step synthetic process. With the technique, it has become easier to screen a biological hit compound and a lead compound having a new structure and optimize structure and activity thereof.
Since the combinatorial chemical synthetic technique carries out most of the reaction procedures on a solid support, successive multi-step reaction and automated reaction are possible. In addition, a high throughput screening (HTS) is made possible because the steps of isolation and purification of products are very simple in this method.
Although the combinatorial chemical synthetic technique solves the uneconomic and inefficient problems of conventional synthetic methods, there are several reasons why this method is not readily applied to the organic synthetic field. One of the representative reasons is that an undesirable side reaction occurs because reagents are used in excessive amounts in most of chemical reactions performed on a solid support and that the range of applicable chemical reactions is limited because employable solvents are restricted depending on the physical property of the solid support. The Merrifield resin and the Wang resin are widely employed as solid support in the combinatorial chemical synthesis. Since these solid supports show a significantly low swelling effect in highly polar solvents such as alcohol and water, selection of reaction solvents is very limited. Accordingly, in order to synthesize various derivatives through solid-phase reaction, selection of a solid support and a linker, optimization of reagents and reaction conditions and selection of a substituent group capable of diversely changing the chemical structure and physical property of the target compound are important factors. Therefore, in order to construct a target compound library using the solid-phase combinatorial chemical synthetic technique, it is necessary to efficiently develop a reaction condition adequate for the characteristics of the target compound and a post-reaction treatment procedure.